The focus of this proposal is to learn the fundamental structural characteristics of Ia antigens of the major histocompatibility complex of the mouse and to understand the molecular basis for immune responsiveness. The relationship between the expression of Ia molecules in F1 hybrids and immune responsiveness will be determined. New highly specific monoclonal antibody reagents will be used in this study. They will be generated by Doolittle's method, using protein sequence data which will be obtained by microsequencing large (CNBr) fragments of Ia polypeptides. These biochemical techniques will also be used to determine whether or not a non-polymorphic (invarient) polypeptide, which co-purifies with Ia, is an intergral part of a functioning Ia molecule. This basic approach should eventually lead to an understanding at a molecular level of the role which Ia antigens play in the control of the immune response. This is a prerequisite for the successful manipulation of the immune response and should result in rational molecular therapies for many varied diseases.